The long term objective of this project is to explore the possibility that a calmodulin-dependent process in brain is altered by repeated cocaine treatments which produce behavioral sensitization in rats. When rats are administered a single dose or repeated injections of a psychomotor stimulant such as cocaine, they exhibit a marked behavioral potentiation to subsequent challenges with the stimulant, an effect which persists several weeks or month after the initial exposure to the drug. A similar phenomenon has also been observed in humans abusing these substances. The motor behaviors (locomotor activity and stereotypy) which are sensitized in rodents by stimulant drugs are mediated through an activation of the mesolimbic and nigrostriatal dopaminergic systems in the forebrain. However, the molecular basis for these long-term or permanent changes in behavior has not been elucidated. Preliminary results with the psychomotor stimulant, amphetamine, have shown the the calcium-binding protein, calmodulin, is markedly increased in striatum from rats receiving chronic, but not acute drug treatments. Calmodulin is a critical regulator of calcium- dependent processes in the central nervous system, and appears to be involved in neurotransmitter synthesis and release, as well as the up- or down-regulation of striatal dopamingeric activity after pharmacological manipulations of this system. In this research plan, we propose to correlate the behavioral effects of chronic cocaine treatments with alterations in the biological activity of calmodulin, as well as the amount of calmodulin and its mRNA, in brain slices, or striatal, mesolimbic, and mesocortical homogenates from rats that have received chronic cocaine treatments. Through these experiments, we will learn more about the mechanism of action of cocaine and the neural basis for the profound alterations in behavior which follow chronic cocaine use. These studies may enable us to understand more fully the possible biochemical mechanisms involved in the powerful drives which lead to or maintain chronic cocaine abuse.